BUFFALO, N.Y. -- Chronic stress has a more powerful effect on
the brain during adolescence than in adulthood and now there's
proof at the molecular level, according to findings published in
Neuron by University at Buffalo researchers.

"We have identified a causal link between molecules and
behaviors involved in stress responses," says Zhen Yan, PhD, a
professor in the Department of Physiology and Biophysics in the UB
School of Medicine and Biomedical Sciences. "It's the first time
that the loss of glutamate receptor has been causally linked to the
negative effects of chronic or repeated stress." A video about the
work is at http://www.youtube.com/watch?v=12TR7nPmnT4

The UB research bolsters the emerging understanding among
neuroscientists that the glutamate system is a key player in mental
illness and, thus, is critical to understanding how to better treat
disorders like depression, anxiety and schizophrenia.

Yan and her colleagues wanted to better understand the molecular
mechanisms of stress, about which little is known. She and her
colleagues had previously found that acute stress helps sharpen
memory (see related story from 2009 at
http://www.buffalo.edu/news/10272). Now they have found that
chronic stress has the opposite effect.

The UB research was conducted on male rats at an age that
corresponds to adolescence in humans, a period when the brain is
highly sensitive to stress. This is especially true of the
prefrontal cortex, which doesn't fully mature until age 25 in
humans and which undergoes dramatic change during adolescence. The
prefrontal cortex is referred to as the "CEO" of the brain,
controlling working memory, decision-making and attention.

In response to repeated stress, Yan and her colleagues found
there was a loss of glutamate receptor expression and function in
the prefrontal cortex. That loss resulted in a significant
impairment in the ability of the adolescent animals to remember and
recognize objects they had previously seen. The same cognitive
deficit was not seen in the similarly stressed adults.

"Because dysfunction in the prefrontal cortex has been
implicated in stress-related mental illness, this research
identifying how stress affects prefrontal cortical functions will
help further unravel how and why mental illnesses occur and how to
treat them," says Yan.

In the same paper, the researchers report that by disrupting the
enzymes that trigger loss of glutamate receptor expression, they
were able to prevent the cognitive impairment induced by repeated
stress exposure.

As a result, the UB researchers have discovered that there may
be a way to prevent the detrimental effects of chronic stress.

Many antipsychotic drugs currently on the market do somehow
affect the glutamate system. Yan and her UB colleagues recently
published research in Molecular Pharmacology, showing how one of
the newer antipsychotics, lurasidone, (trade name Latuda) does just
that. But, she notes, many of these drugs also affect other
important neurotransmitter systems as well.

"If, based on this research, we can begin to target the
glutamate system in a more specific and effective way, we might be
able to develop better drugs to treat serious mental illness," she
says.

The research is especially significant because with some mental
disorders, such as schizophrenia, onset typically occurs in late
adolescence.

"While there have been many behavioral studies about stress,
understanding stress at a molecular level is key to developing
strategies to prevent stress-induced behavioral deficits," says
Yan. "In the end, it has to be boiled down to molecules. Without
knowing why something happens at a molecular level, you cannot do
anything about it."

In addition to Yan, co-authors are: Eunice Y. Yuen, PhD,
research assistant professor, Jing Wei, PhD, research scientist,
Wenhua Liu, PhD, research scientist, Ping Zhong, PhD, research
scientist, and Xiangning Li, PhD, postdoctoral associate, all in
the Department of Physiology and Biophysics in the UB School of
Medicine and Biomedical Sciences.

The research was funded by the National Institutes of Mental
Health of the NIH.